JP6154718B2 - Lower urinary tract disease treatment - Google Patents
Lower urinary tract disease treatment Download PDFInfo
- Publication number
- JP6154718B2 JP6154718B2 JP2013208646A JP2013208646A JP6154718B2 JP 6154718 B2 JP6154718 B2 JP 6154718B2 JP 2013208646 A JP2013208646 A JP 2013208646A JP 2013208646 A JP2013208646 A JP 2013208646A JP 6154718 B2 JP6154718 B2 JP 6154718B2
- Authority
- JP
- Japan
- Prior art keywords
- bladder
- cystitis
- prostatitis
- pain
- urinary tract
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000003741 urothelium Anatomy 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4704—2-Quinolinones, e.g. carbostyril
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
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- Organic Chemistry (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Description
本発明は、下部尿路疾患、特に間質性膀胱炎の治療剤に関する。 The present invention relates to a therapeutic agent for lower urinary tract disease, particularly interstitial cystitis.
下部尿路障害は下部尿路機能に関する異常の総称であり、下部尿路障害に起因する症状である下部尿路症状は、主に蓄尿症状(頻尿や尿意切迫感など)、排尿症状(尿勢低下や尿線分割など)、及び排尿後症状(残尿感や排尿後尿滴下など)の3種類に大別される。また、下部尿路症状には排尿痛、膀胱痛、及び尿道痛などの下部尿路痛、排尿筋過活動、及び排尿困難などが含まれ、下部尿路障害に際して血尿が認められることがある。下部尿路障害の原因となる疾患(下部尿路疾患)としては、前立腺肥大症、前立腺炎、前立腺症、膀胱頸部硬化症、過活動膀胱、慢性膀胱炎、間質性膀胱炎、膀胱痛症候群などが挙げられる。 Lower urinary tract disorder is a general term for abnormalities related to lower urinary tract function. Lower urinary tract symptoms, which are symptoms caused by lower urinary tract disorders, are mainly urinary symptoms (such as frequent urination and urgency), urination symptoms (urine Dysfunction and urinary division), and post-urination symptoms (residual urine sensation, post-urination dripping, etc.). In addition, lower urinary tract symptoms include lower urinary tract pain such as micturition pain, bladder pain, and urethral pain, detrusor overactivity, dysuria, etc., and hematuria may be observed in lower urinary tract disorders. Diseases that cause lower urinary tract disorders (lower urinary tract diseases) include prostatic hypertrophy, prostatitis, prostate disease, bladder cervical sclerosis, overactive bladder, chronic cystitis, interstitial cystitis, bladder pain Syndrome etc. are mentioned.
これらのうち、特に間質性膀胱炎(Interstitial Cystitis)は、頻尿、尿意亢進、尿意切迫感、膀胱不快感及び膀胱痛などの症状を呈する、尿路感染症や他の明らかな病的状態が認められない難治性疾患である。女性により多く発症するが、性別・年齢を問わず発症し、患者数は我国では25万人以上、米国では100万人以上と推定されている。しかし、間質性膀胱炎の定義や診断基準に関しては未だ世界的な統一された見解が示されておらず、膀胱痛症候群(Bladder pain syndrome:BPS)、過敏性膀胱症(Hypersensitive bladder syndrome :HBS)といわれることもある。
また、非細菌性慢性前立腺炎(chronic nonbacterial prostatitis)は、前立腺の炎症が慢性的に続いている状態で、慢性前立腺炎の90%を占める疾患である。間質性膀胱炎と併発することが多く、陰嚢部などの鈍痛や不快感、また頻尿、排尿時痛、残尿感などの排尿症状である。射精前後に痛みの症状を呈する等、間質性膀胱炎に類似している。非細菌性慢性前立腺炎の患者は男性に限定されるが、間質性膀胱炎よりも患者数は多く、70〜100万人といわれている。
Of these, interstitial cystitis, in particular, is a urinary tract infection and other obvious pathological conditions that present symptoms such as frequent urination, increased urinary urgency, urgency, bladder discomfort, and bladder pain. This is an intractable disease that is not recognized. It develops more frequently in women, but it occurs regardless of gender and age, and the number of patients is estimated to be over 250,000 in Japan and over 1 million in the United States. However, there is still no globally unified view on the definition and diagnostic criteria for interstitial cystitis. Bladder pain syndrome (BPS), Hypersensitive bladder syndrome (HBS) ) Is sometimes said.
Non- bacterial prostatitis (chronic nonbacterial prostatitis) is a disease that accounts for 90% of chronic prostatitis in a state where inflammation of the prostate is chronically continued. It often accompanies interstitial cystitis, dull pain and discomfort in the scrotum, etc., and urination symptoms such as frequent urination, pain during urination, and residual urine sensation. It resembles interstitial cystitis, with symptoms of pain before and after ejaculation. Although the number of patients with non- bacterial chronic prostatitis is limited to men, the number of patients is more than that of interstitial cystitis, which is said to be 70 to 100 million.
間質性膀胱炎や非細菌性慢性膀胱炎の原因としては、肥満細胞の活性化、グリコサミノグリカン層異常、尿路上皮における細胞増殖阻害、自己免疫、神経原性炎症、一酸化窒素代謝、毒性物質、低酸素状態などが考えられているが、明確な原因は未だ特定されていない。
間質性膀胱炎では膀胱の非特異的な慢性炎症を伴うことが多いが、ステロイド等の抗炎症剤は本疾患及び本疾患の動物モデルに有効性を示さないことから、炎症そのものが本疾患における頻尿などの症状を引き起こしているのではないと考えられている。これら疾患の原因が未だ不明であることから治療薬の開発を困難としている。現在治療に用いられている薬物としては、抗ヒスタミン薬、抗うつ薬、シメチジン、抗生物質、ステロイド、ペントサン・ポリサルフェートなどがあるが、いずれも対症療法であり、有効な治療方法とはなっていない。唯一原因療法として期待されるものにトシル酸スプラタストがあるが、その効果は未だ十分ではない。
Causes of interstitial cystitis and non-bacterial chronic cystitis include activation of mast cells, abnormal glycosaminoglycan layer, inhibition of cell proliferation in urothelium, autoimmunity, neurogenic inflammation, nitric oxide metabolism Toxic substances, hypoxia, etc. are considered, but no clear cause has been identified yet.
Interstitial cystitis is often accompanied by nonspecific chronic inflammation of the bladder, but anti-inflammatory drugs such as steroids are not effective in this disease and animal models of this disease. It is thought not to cause symptoms such as frequent urination in Japan. The cause of these diseases is still unknown, making it difficult to develop therapeutic drugs. Drugs currently used for treatment include antihistamines, antidepressants, cimetidine, antibiotics, steroids, and pentosan polysulfate, all of which are symptomatic and are not effective treatments. Absent. The only promising causal therapy is suplatast tosylate, but the effect is not yet sufficient.
このように、間質性膀胱炎は他の膀胱炎等と異なり、抗生物質や抗菌剤を使用しても効果がない。間質性膀胱炎は大変な激痛を伴うにもかかわらず、現時点で有用な治療薬がない状況であり、最終的に膀胱摘出を行わざるを得ない症例も存在する。そのため、多くの患者がこれらの症状で日常生活が著しく障害されたままとなっている。 Thus, interstitial cystitis is different from other cystitis and the like and has no effect even when antibiotics or antibacterial agents are used. Although interstitial cystitis is accompanied by severe pain, there is no useful therapeutic agent at the present time, and there are cases where cystectomy is ultimately required. As a result, many patients remain severely impaired in their daily lives due to these symptoms.
なお、間質性膀胱炎は診断自体も難しく、かつ激痛を伴うものであったため、本発明者は、間質性膀胱炎の患者の負担を軽減すべく、電流知覚閾値検査装置(CPT装置)に接続されて使用され、尿道に挿入されて膀胱内を診断可能な間質性膀胱炎診断用カテーテル(特許文献1)、間質性膀胱炎を診断する方法(特許文献2)、間質性膀胱炎の診断に使用される尿道保護器具(特許文献3)などを発明してきた。しかし、上述の通り、有用な治療薬が存在しない。 In addition, since the interstitial cystitis is difficult to diagnose itself and is accompanied by severe pain, the present inventor has developed a current perception threshold test device (CPT device) in order to reduce the burden on the patient with interstitial cystitis. Catheter used for diagnosis of interstitial cystitis (Patent Document 1), a method for diagnosing interstitial cystitis (Patent Document 2), interstitial We have invented a urethral protection device (Patent Document 3) used for diagnosis of cystitis. However, as mentioned above, there are no useful therapeutic agents.
そこで、本発明の課題は、下部尿路疾患、特に間質性膀胱炎に効果のある新たな治療薬及び治療方法を提供することを目的とする。 Therefore, an object of the present invention is to provide a new therapeutic agent and method effective for lower urinary tract disease , particularly interstitial cystitis.
上記課題を解決するため、本発明の下部尿路疾患治療剤は、有効成分がレバミピドであることからなる。
また、有効成分が2−(4−クロルベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸またはその塩であることからなる。
In order to solve the above-mentioned problems, the therapeutic agent for lower urinary tract disease of the present invention consists of rebamipide as an active ingredient.
The active ingredient is 2- (4-chlorobenzoylamino) -3- (2-quinolon-4-yl) propionic acid or a salt thereof.
さらに、本発明の製剤は、2−(4−クロルベンゾイルアミノ)−3−(2−キノロン−4−イル)プロピオン酸またはその塩および膀胱用製剤担体を含有することからなる。好ましくは、製剤が液状又は懸濁状の製剤、又は注射剤であることからなる。 Further, the preparation of the present invention comprises 2- (4-chlorobenzoylamino) -3- (2-quinolon-4-yl) propionic acid or a salt thereof and a pharmaceutical preparation for bladder. Preferably, the preparation is a liquid or suspension preparation, or an injection.
さらに、本発明は間質性膀胱炎治療剤を製造するためのレバミピドまたはその医薬的に許容される塩の使用、間質性膀胱炎の治療に使用するためのレバミピドまたはその医薬的に許容される塩、間質性膀胱炎の患者に、治療上の有効量のレバミピドまたはその医薬的に許容される塩を投与することを特徴とする間質性膀胱炎の治療方法を含む。さらに、本発明は間質性膀胱炎以外の下部尿路疾患にも有用な治療薬及び治療方法を含む。 Furthermore, the present invention relates to the use of rebamipide or a pharmaceutically acceptable salt thereof for producing an agent for treating interstitial cystitis, rebamipide or a pharmaceutically acceptable salt thereof for use in the treatment of interstitial cystitis. A method of treating interstitial cystitis comprising administering a therapeutically effective amount of rebamipide or a pharmaceutically acceptable salt thereof to a patient suffering from interstitial cystitis. Furthermore, the present invention includes therapeutic agents and methods useful for lower urinary tract diseases other than interstitial cystitis.
すなわち、本発明者等は、鋭意研究の結果、現在胃潰瘍や点眼薬として使用されているレバミピドが下部尿路疾患、特に間質性膀胱炎の治療に効果があること、及び他の膀胱炎や前立腺炎の治療に有効であることを発見し、本発明を完成させたものである。 That is, as a result of intensive studies, the present inventors have found that rebamipide currently used as a gastric ulcer and eye drops is effective in treating lower urinary tract diseases, particularly interstitial cystitis, and other cystitis and The present invention has been completed by discovering that it is effective in treating prostatitis .
レバミピド(rebamipide)は、下記式(I)
上記レバミピドの医薬的に許容される塩としては、生理的または薬学的に許容される種々の塩が使用できる。例えば、水酸化ナトリウム、水酸化カリウム、トロメタモール、モノエタノールアミン、ジエタノールアミン、トリエタノールアミン、ジイソプロパノールアミン、メグルミン等と共に形成した塩が挙げられる。 As the pharmaceutically acceptable salt of rebamipide, various physiologically or pharmaceutically acceptable salts can be used. Examples thereof include salts formed with sodium hydroxide, potassium hydroxide, trometamol, monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine, meglumine and the like.
本発明の治療薬は、レバミピドまたはその塩を有効成分とし、一般的な医薬製剤の形態に調製される。例えば、通常使用される充填剤、増量剤、結合剤、付湿剤、崩壊剤、表面活性剤、滑沢剤などの希釈剤あるいは賦形剤を用いて調製される。この医薬製剤の形態としては、液剤、注射剤、懸濁剤、錠剤、散剤、乳剤、顆粒剤、カプセル剤、エアロゾール剤など公知の様々な形態が挙げられるが、下部尿路疾患、特に間質性膀胱炎の治療にあたっては膀胱に直接注入することが好ましいために、液剤、懸濁剤、又は注射剤の形態であることが望ましい。 The therapeutic agent of the present invention contains rebamipide or a salt thereof as an active ingredient and is prepared in the form of a general pharmaceutical preparation. For example, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants and the like. Examples of the form of this pharmaceutical preparation include various known forms such as liquids, injections, suspensions, tablets, powders, emulsions, granules, capsules, aerosols, etc. In the treatment of qualitative cystitis, since it is preferable to inject directly into the bladder, it is preferably in the form of a solution, suspension, or injection.
注射剤として調製される場合には、液剤、乳剤または懸濁剤として調製される。通常の注射剤と同様に殺菌されて無菌化され、かつ血液と等張であるのが好ましい。液剤、乳剤および懸濁剤の形態に関して使用される希釈剤としては、一般的に公知又は慣用されているものを使用できる。例えば水、エトキシ化イソステアリルアルコール、エチルアルコール、プロピレングリコール、ポリオキシエチレンソルビタン脂肪酸エステル類などを使用できる。また、食塩、ブドウ糖、グリセリンを使用して等張性の溶液を調製しても良い。また、必要であれば溶解補助剤、緩衝剤、無痛化剤、保存剤、着色剤などを使用することが可能である。 When prepared as an injection, it is prepared as a solution, emulsion or suspension. It is preferably sterilized and sterilized in the same manner as normal injections and isotonic with blood. As the diluent used in the form of a solution, an emulsion and a suspension, those generally known or commonly used can be used. For example, water, ethoxylated isostearyl alcohol, ethyl alcohol, propylene glycol, polyoxyethylene sorbitan fatty acid esters and the like can be used. Alternatively, isotonic solutions may be prepared using salt, glucose, and glycerin. If necessary, a solubilizing agent, a buffering agent, a soothing agent, a preservative, a coloring agent, and the like can be used.
溶解補助剤は、例えばカルボキシメチルセルロースナトリウム、ポリオキシエチレンラウリルエーテル、ポリオキシエチレングリコールエーテル類、ポリエチレングリコール高級脂肪酸エステル類、ポリオキシエチレンソルビタンモノラウレート、ポリオキシエチレン脂肪酸エステルなどである。緩衝剤は、例えばリン酸ナトリウム、リン酸水素ナトリウム、リン酸水素カリウム、硼酸ナトリウム、クエン酸、クエン酸ナトリウム、酒石酸、酒石酸ナトリウム、酢酸、酢酸ナトリウム、イプシロンアミノカプロン酸、グルタミン酸ナトリウムなどである。抗酸化剤は、例えば亜硫酸ナトリウム、ピロ亜硫酸ナトリウム、重亜硫酸ナトリウム、チオ亜硫酸ナトリウム、アスコルビン酸などである。防腐剤は、例えばクロロブタノール、塩化ベンザルコニウム、塩化ベンゼトニウム、フェニル水銀塩、チメロサル、フェネチルアルコール、メチルパラベン、プロピルパラベンなどである。等張化剤は、例えば食塩、ブドウ糖、D−マンニトール、グリセリンなどである。溶解剤は、N−メチルグルカミンなどである。pH調整剤は、例えば水酸化ナトリウム、塩酸などである。 Examples of the solubilizer include sodium carboxymethyl cellulose, polyoxyethylene lauryl ether, polyoxyethylene glycol ethers, polyethylene glycol higher fatty acid esters, polyoxyethylene sorbitan monolaurate, and polyoxyethylene fatty acid esters. Examples of the buffer include sodium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium borate, citric acid, sodium citrate, tartaric acid, sodium tartrate, acetic acid, sodium acetate, epsilon aminocaproic acid, sodium glutamate and the like. Examples of the antioxidant include sodium sulfite, sodium pyrosulfite, sodium bisulfite, sodium thiosulfite, ascorbic acid and the like. Examples of the preservative include chlorobutanol, benzalkonium chloride, benzethonium chloride, phenylmercury salt, thimerosal, phenethyl alcohol, methylparaben, propylparaben, and the like. Examples of isotonic agents are sodium chloride, glucose, D-mannitol, glycerin and the like. Examples of the solubilizer include N-methylglucamine. Examples of the pH adjuster include sodium hydroxide and hydrochloric acid.
本発明は、懸濁液(点眼薬)として市販されている形態を使用することが可能である。懸濁液(点眼薬)は、レバミピドを滅菌蒸留水など基剤と混合し、滅菌処理して製造される。また、公知又は慣用されている溶解補助剤、緩衝剤、防腐剤、等張化剤、pH調整剤などが必要に応じて配合される。市販されている具体的な形態としては、有効成分として1ml中にレバミピドを20mg含む。また、ポリビニルアルコール(部分けん化物)、クエン酸ナトリウム水和物、塩化ナトリウム[等張化剤]、塩化カリウム[等張化剤]、塩酸[pH調整剤]、水酸化ナトリウム[pH調整剤]、精製水を添加物として含み、pHは5.5〜6.5、浸透圧比は0.9〜1.1(生理食塩液に対する比)である。このような懸濁液(例えば、20ml程度)を、患者の膀胱の状況などに応じて、注射器やカテーテルなどを介して膀胱に必要量注入して使用する。ただし、間質性膀胱炎の治療に効果のある限り、形態、濃度、使用回数、投与量は上記の形態のみに限定されるものではなく、患者の膀胱の状況などに応じて適宜選択することが可能である。 In the present invention, it is possible to use a form that is commercially available as a suspension (eye drops). Suspensions (eye drops) are produced by mixing rebamipide with a base such as sterilized distilled water and sterilizing. In addition, known or commonly used solubilizers, buffers, preservatives, isotonic agents, pH adjusters and the like are blended as necessary. As a concrete form marketed, 20 mg of rebamipide is contained in 1 ml as an active ingredient. In addition, polyvinyl alcohol (partially saponified product), sodium citrate hydrate, sodium chloride [isotonizing agent], potassium chloride [isotonizing agent], hydrochloric acid [pH adjusting agent], sodium hydroxide [pH adjusting agent] Purified water is included as an additive, pH is 5.5 to 6.5, and osmotic pressure ratio is 0.9 to 1.1 (ratio to physiological saline). Such a suspension (for example, about 20 ml) is used by injecting a necessary amount into the bladder via a syringe, a catheter or the like according to the condition of the patient's bladder. However, as long as it is effective in the treatment of interstitial cystitis, the form, concentration, number of uses, and dose are not limited to the above forms, but should be appropriately selected according to the condition of the patient's bladder, etc. Is possible.
下記実施例の全ての患者は、内視鏡的に間質性膀胱炎と診断され、かつ日本で唯一認可されている膀胱水圧拡張術も無効であり、痛みが持続している患者である。具体的には、4%キシロカイン単剤、又は4%キシロカイン20ml+アミカシン100ml+サクシゾン300mgを注入しても、痛みが持続している患者である。
治療の内容は、ムコスタ(登録商標)点眼薬を28本使用し、約8ccを注射器に入れ、カテーテルを使用して膀胱内に注入したものである(1時間以上)。
All patients in the following examples are patients who have been diagnosed endoscopically as interstitial cystitis and who have been unable to use the only Japanese approved hydrostatic bladder expansion technique, and who have sustained pain. Specifically, it is a patient whose pain persists even after injecting 4% xylocaine alone or 4% xylocaine 20 ml + amikacin 100 ml + succinone 300 mg.
The contents of treatment were 28 mucosta (registered trademark) eye drops, about 8 cc placed in a syringe, and injected into the bladder using a catheter (1 hour or more).
80歳(男性) 平成24年4月9日初診
主訴は蓄尿時膀胱痛及び尿道痛、非細菌性慢性前立腺炎を併発
某市立病院において膀胱水圧拡張術を行うも再発
膀胱痛が強いため、平成25年7月24日及び31日に上記治療を行った。
その結果、現在まで痛みが消失。膀胱潰瘍も内視鏡写真で容易に視認できるほど明らかに改善した(図1及び図2)。副作用は見受けられなかった。
80 years old (male) The chief complaint on April 9, 2012 was urinary bladder pain and urethral pain, and non-bacterial chronic prostatitis. The treatment was performed on July 24 and 31, 2013.
As a result, pain has disappeared until now. The bladder ulcer was also clearly improved so that it could be easily recognized by endoscopic photographs (FIGS. 1 and 2). There were no side effects.
79歳(女性) 平成24年4月2日初診
平成25年7月26日、29日、30日、31日、8月2日、3日の6回上記治療を行った。
その結果、現在まで痛みが消失。膀胱潰瘍も膀胱潰瘍も内視鏡写真で容易に視認できるほど明らかに改善した(図3及び図4)。副作用は見受けられなかった。
79 years old (female) First visit on April 2, 2012
The above treatment was carried out 6 times on July 26, 29, 30, 30, 31, August 2, 2013 and 2013.
As a result, pain has disappeared until now. Both bladder ulcer and bladder ulcer were clearly improved so that they could be easily seen with endoscopic photographs (FIGS. 3 and 4). There were no side effects.
74歳(男性) 平成24年6月11日初診
非細菌性慢性前立腺炎を併発
平成25年7月29日に上記治療を行った。
その結果、現在まで痛みが消失。副作用は見受けられなかった。
74 years old (male) The above treatment was carried out on July 29, 2013, which was accompanied by non-bacterial chronic prostatitis on June 11, 2012.
As a result, pain has disappeared until now. There were no side effects.
以上の通り、これまで難病とされ確かな治療方法が存在しない間質性膀胱炎について、いずれも治療に効果があったことが明白である。さらに、併発していた非細菌性慢性前立腺炎についても治療効果が見受けられた。なお、診断及び膀胱注入にあたっては、上述の本発明者の過去の発明を使用することにより、患者の痛みなく行うことが可能である。したがって、診断から治療まで、患者の負担なく行うことが可能となった。また、治療前には患者に内容を説明するとともに文書で同意を得た。 As described above, it is clear that all of interstitial cystitis, which has been treated as an intractable disease and has no reliable treatment method, was effective in the treatment. In addition, a therapeutic effect was also seen for non-bacterial chronic prostatitis that occurred concurrently. Diagnosis and bladder injection can be performed without pain of the patient by using the above-described invention of the present inventors. Therefore, it has become possible to perform from diagnosis to treatment without burden on the patient. Prior to treatment, the patient was explained to the patient and written consent was obtained.
さらに、本発明の膀胱炎への効果についてラット慢性膀胱炎モデルを使用して実験を行った。 Further, the effect of the present invention on cystitis was examined using a rat chronic cystitis model.
方法
12週齢雌性SDラットを用い、isoflurane麻酔下にcyclophosphamide(150mg/kg)を腹腔内投与し、直後にレバミピド(1mMまたは10mM、300μL)またはvehicleを膀胱注入し、1時間仰臥位を保持した。
(1)2日後に覚醒下膀胱内圧測定(生食灌流速度0.04ml/min)を行った。
(2)2日後に膀胱を摘出し、H&E染色を行い、炎症の程度をスコア化した。
(3)膀胱組織中の炎症性サイトカインであるTNFα、IL-6とIL-1βをRT-PCRにて、炎症マーカーであるMPOをELISAにて計測した。
Method
Using 12-week-old female SD rats, cyclophosphamide (150 mg / kg) was intraperitoneally administered under isoflurane anesthesia, and immediately after that, rebamipide (1 mM or 10 mM, 300 μL) or vehicle was instilled into the bladder, and the supine position was maintained for 1 hour.
(1) Two days later, awake intravesical pressure was measured (saline perfusion rate 0.04 ml / min).
(2) Two days later, the bladder was removed and subjected to H & E staining, and the degree of inflammation was scored.
(3) TNFα, IL-6 and IL-1β, which are inflammatory cytokines in bladder tissue, were measured by RT-PCR, and MPO, which is an inflammatory marker, was measured by ELISA.
結果
(1)膀胱内圧試験ではコントロールに比べ(22.4±2.3 min)、CYP群で排尿間隔の短縮を認め(10.7±0.7 min)、レバミピド群では容量依存的に排尿間隔の延長を認めた(1mM群;14.4±2.1 min、10mM群21.1±2.5 min)。
(2)粘膜下の浮腫、炎症細胞の浸潤はCYP群で有意に高く、レバミピド群において有意に軽減された。
(3)膀胱組織中のTNFα、IL-6、IL-1β、MPOはCYP群で有意に高く、レバミピド群で上昇が抑制された。
結論
レバミピドの膀胱注入により膀胱の炎症は抑制され、排尿間隔の延長を認めた。
Results (1) In the bladder pressure test, the urination interval was shortened in the CYP group (10.7 ± 0.7 min) compared to the control (22.4 ± 2.3 min), and the urination interval was increased in the rebamipide group in a dose-dependent manner (1 mM) Group: 14.4 ± 2.1 min, 10 mM group 21.1 ± 2.5 min).
(2) Submucosal edema and inflammatory cell infiltration were significantly higher in the CYP group and significantly reduced in the rebamipide group.
(3) TNFα, IL-6, IL-1β, and MPO in the bladder tissue were significantly higher in the CYP group, and the increase was suppressed in the rebamipide group.
Conclusion Bladder injection of rebamipide suppressed bladder inflammation and prolonged urination interval.
上記のとおり、本発明は間質性膀胱炎のみならず、非細菌性慢性膀胱炎や他の膀胱炎、非細菌性慢性前立腺炎にも有効であり、慢性膀胱炎、前立腺肥大症、非細菌性慢性前立腺炎、前立腺炎、前立腺症、膀胱頸部硬化症、過活動膀胱等を含む下部尿路疾患に有効であると解される。 As described above, the present invention is effective not only for interstitial cystitis but also for non-bacterial chronic cystitis, other cystitis, and non-bacterial chronic prostatitis . Chronic cystitis, prostatic hypertrophy, non-bacteria It is understood that it is effective for lower urinary tract diseases including chronic chronic prostatitis, prostatitis, prostatitis, bladder neck sclerosis, overactive bladder and the like.
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